New V1a receptor antagonist. Part 2. Identification and optimization of triazolobenzazepines

Discovery and Characterization of RGH-122, a Potent, Selective, and Orally Bioavailable V1a Receptor Antagonist

“…In the case of the isopropylamino derivatives, introducing other substituents to position 8 resulted in equipotent (36), slightly weaker (37−40), and weaker (41,42) molecules (Table 5). In contrast, analogues of compound 43 were highly effective (K i < 1 nM, IC 50 < 2.5 nM), independent of the groups in position 8; therefore the ideal substituent was finally determined by in vivo functional measurements.…”

“…Step 10. 8-Bromo-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2,4]triazolo [4,3-a][1]benzazepine-5amine (36). Prepared from 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2,4]triazolo [4,3-a][1]benzazepine-5amine (I-13b) and acetone according to the procedure described in the synthesis of compound 15.…”

“…28−30 Despite the positive clinical results and ongoing studies in other indications, 31−33 the use of conivaptan is currently limited to treating hyponatremia, while tolvaptan is also applied to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). 34,35 In our previous communications, we published the identification of [1,2,4]triazolo [4,3-a][1]benzazepine (8) 36 and imidazo [1,2-a]triazolo [4,3-c] [1,3]diazepine (9) 37 derivatives, which were found to be selective V1a antagonists having remarkable efficacy in vivo (Table 1), as well. Inspired by these results our aim was to develop novel and selective V1a antagonists having similar or even better efficacy than 5.…”

Synthesis and Characterization of New V1A Antagonist Compounds: The Separation of Four Atropisomeric Stereoisomers

“…The 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)-aided ring closure of 14a−g yielded the key intermediates 15a−g. Unlike as reported in our previous publication (ref 11), lactam 15 was first converted to a methoxy derivative using trimethyloxonium tetrafluoroborate and then the R 1 group was introduced by allowing the methoxy analogues to react with the appropriate acid hydrazide. Deprotection of these dioxolane derivatives 16 resulted in the 17 oxo analogues, from which the racemic 5-hydroxy compounds (5, 18−20, 29−30) were prepared by reduction using sodium borohydride.…”

“…10 Recently, we reported the synthesis and characterization of a triazolobenzazepine derivative (4) showing strong V 1A antagonist activity, high selectivity toward the V 2 receptor, and in vivo oral activity at a 30 mg/kg dose. 11 Exploring further the medicinal chemistry of this class of compounds, particularly with a view to gaining new empirical data that can facilitate a better understanding of the pertinent structure− activity relationships (SAR), compound 5 was synthesized as a first step (Table 1), in which a hydroxyl group was introduced to the C-5 position of 4. Although the homology models we had used earlier 12 suggested a preference for apolar substituents at this position of the core, 5 was found to be a potent and selective V 1A antagonist (see the Molecular Modeling section for the resolution of this apparent contradiction).…”